This NIAAA Alcohol Research Center (ARC) Grant is the catalytic element that integrates a large group of investigators across the University of North Carolina at Chapel Hill (UNC). The UNC School of Medicine Bowles Center for Alcohol Studies (BCAS), provides a foundation of administrative support and dedicated Bowles building space for alcohol research. The UNC ARC fosters interdisciplinary collaborative research on alcohol use disorders, alcohol abuse and the impact of alcohol on health and disease - exactly the goal of an NIAAA ARC. The ARC has facilitated the growth and development of UNC into an outstanding alcohol research University, among the best in the world. Research and education have always centered on a theme of molecular and cellular pathology in alcohol use disorders. This renewal focuses on the molecular mechanisms that underlie alcohol-induced circuit pathology across the stages of addiction. Ultimately, our guiding hypothesis is that alcohol-induced dysregulation of neural circuitry drives pathological behaviors and is thus the key cause of all alcohol-related pathology. This 4th renewal of the UNC ARC continues an emphasis on alcohol use disorder pathology, integrating existing and new faculty to investigate changes in neural circuits and molecular signaling in models of drinking across the proposed stages of addiction. The scope of these studies addresses the critical neurobiological changes leading to all alcoholic pathologies, i.e. the mechanisms leading to heavy chronic drinking. The ARC integrates multiple signaling systems and neurocircuits that each focus on specific mechanisms within and across brain regions. The research components also include the translational endpoint, functional magnetic resonance imaging (fMRI) connectivity of each component?s pathological circuit model in the Scientific Resource Core. This approach is expected to increase discovery, improve models and gain strength from common assessments across preclinical models to the ARC human studies. The ARC through the Information Translation Core informs practicing health professionals, health professional and college students as well as youth through specific alcohol curricula for each group to have the greatest impact on health. This proposal connects principle investigators of involving 15 independent funded faculty. By design, each research component of this ARC will focus on specific models that capture distinct endophenotypes associated with alcohol abuse. A range of molecular mechanisms that drive these circuit alterations will be explored, including kinases, cytokines and neuropeptides. This ARC renewal continues to be the catalytic element that integrates a broad group of investigators, pairing senior and junior faculty within ARC components that promote discovery across the BCAS and UNC as well as educating many within NC. This ARC proposal continues a research focus on pathogenesis of alcohol addiction with emphasis on molecular and circuit mechanisms that lead to dysfunctional brain networks, a theme at the cutting edge of neuroscience. The ARC will conduct, promote, support, and mentor research on the pathology of alcohol use disorders and educate broad groups of the public, including health professionals, families, college students and youth in North Carolina on the causes and prevention of these disorders.